SUMMARY Atherosclerosis and its consequences are the most common causes of death worldwide. Lipid accumulation and associated inflammatory processes are critical to atherosclerosis progression. Investigators from Projects 1 and 2 recently observed that chronic psychosocial stress accelerates hematopoiesis and promotes inflammation in atherosclerotic mice. It is currently unknown if this is relevant in humans. Post-traumatic stress disorder (PTSD), triggered by exposure to extreme traumatic events, is associated with elevated circulating markers of inflammation and higher risk for MI. PTSD patients therefore provide a unique opportunity to study the mechanisms linking chronic psychosocial stress and atherosclerosis. In Project 3 we will employ innovative PET combined with magnetic resonance imaging (PET/MRI) to simultaneously study the hematopoietic system, the artery wall, and the brain's fear system, which comprises the amygdala and anterior cingulate cortex (ACC), to elucidate the relationship between psychosocial stress and systemic inflammation/atherosclerosis in a two center clinical study looking at: I) individuals with PTSD, II) individuals without PTSD but with exposure to severe psychosocial trauma (Trauma Control), and III) matched volunteers with neither PTSD nor exposure to trauma (Healthy Control). Participants in the three study groups, recruited from urban settings in New York and Boston, will be group-matched by age, gender, and Framingham risk scores (FRS). We will recruit 80 subjects in each group and in Aim 1, investigate the relationship between PTSD and atherosclerotic inflammation and burden measured by PET/MRI. In Aim 2, we will examine the relationships between brain's fear circuit responsiveness to threat assessed by functional MRI (fMRI) and white matter integrity assessed by diffusion tensor imaging (DTI) and relate these data to hematopoietic system activation, and vascular inflammation measured by fluorodeoxyglucose (FDG)-PET and atherosclerotic burden measured by MRI. Additionally these parameters will also be related to blood hematopoietic progenitor migration measured using multiparametric fluorescence-activated cell sorting (FACS). Together, these data will provide a very unique picture of the multi-system link between the human brain, hematopoietic organs, inflammatory cells, and the artery wall.